Transdermal formulation for the treatment of pain and/or inflammation

ABSTRACT

Described herein are transdermal formulations of phytocannabinoids and methods of using the same in the treatment of pain and/or inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/457,746, filed Jun. 28, 2019, which is incorporated by referenceherein in its entirety.

BACKGROUND

The present technology relates generally to the field of transdermalformulations for the treatment of pain.

SUMMARY

In one aspect, provided herein is a transdermal formulation comprisingabout 0.05% w/w to about 50% w/w phytocannabinoid dispersed in apharmaceutically acceptable carrier comprising:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In some embodiments, the formulation is a topical formulation. In someembodiments, the topical formulation is a semi-solid formulationselected from a gel, a lotion, a cream, an ointment, a serum, or a foam.

In some embodiments, the phytocannabinoid is selected from cannabidiol(CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN),cannabitriol (CBT), cannabidiolic acid (CBDA), cannabigerolic acid(CBGA), cannabidivarin (CBDV), beta caryophyllene, andtetrahydrocannabinol, or any combination thereof. In some embodiments,the cannabidiol is microencapsulated cannabidiol. In some embodiments,the microencapsulated cannabidiol comprises cannabidiol encapsulatedwithin liposomes.

In some embodiments, the penetration enhancer comprises diethyleneglycol monoethyl ether, lauryl alcohol, dimethyl sulfoxide (DMSO),dimethyl acetamide, N-methyl pyrrolidone, oleic acid, azone,oxazolidinone derivative, urea, terpene, or any combination thereof.

In some embodiments, the thickening agent comprises a cross-linkedpolyacrylic acid polymer; a cellulose derivative; xanthan gum, locustbeam gum, guar gum or derivative thereof; alginic acid; inorganicpolymer; PEMULEN™ (a copolymer of acrylic acid and C10-C30 alkylacrylate cross-linked with allyl pentaerythritol); or any combinationthereof.

In some embodiments, the buffering agent comprises triethanolamine,potassium hydroxide, cocoamidodiethylamine, or any combination thereof.

In some embodiments, the sequestering agent comprises EDTA, or a saltand/or solvate thereof; citric acid; tartaric acid; or any combinationthereof.

In some embodiments, the preservative comprises phenoxyethanol, a ureaderivative, ethylhexylglycerine, hydantoin, benzoic, sorbic acid, anisicacid, or any combination thereof.

In one aspect, provided herein is a transdermal formulation consistingof microencapsulated cannabidiol dispersed in a pharmaceuticallyacceptable carrier consisting of deionized water, a penetrationenhancer, a thickening agent, a buffering agent, a sequestering agent,and a preservative. In some embodiments, the formulation is topicalformulation. In some embodiments, the topical formulation is asemi-solid formulation selected from a gel, a lotion, a cream, anointment, a serum, or a foam. In some embodiments, the formulationconsists of about 0.20% w/w cannabidiol, about 18% w/w diethylene glycolmonoethyl ether, about 1% w/w cross-linked polyacrylic acid polymer,about 0.3% w/w triethanolamine, about 0.5% w/w phenoxyethanol, about0.05% w/w disodium EDTA dihydrate, and q.s. deionized water; wherein thecannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein is a method of treatingmusculoskeletal pain and/or inflammation in a subject in need thereof,the method comprising topically administering to one or more regions ofskin on the subject a therapeutically effective amount of a transdermalformulation described herein. In some embodiments, the transdermalformulation is administered by topical application to the region of skinon the subject without microneedle delivery. In some embodiments, thetransdermal formulation is administered once every hour for an initialperiod of three hours for a total of four applications and thensubsequently administered 3-4 times per day. In some embodiments, themusculoskeletal pain and/or inflammation is located at one or more ofthe foot, ankle, knee, hip, hand, wrist, elbow, neck, scalp, back,chest, abdomen, shoulder, arm, or leg, of the subject.

In another aspect, provided herein is a method for relieving painassociated with osteoarthritis of one or more joints in a subject inneed thereof, the method comprising topically administering atherapeutically effective amount of a transdermal formulation describedherein to one or more regions of skin covering the one or more joints onthe subject. In some embodiments, the one or more joints are located atone or more of the foot, ankle, knee, hip, hand, wrist, elbow, neck,back, or shoulder of the subject. In some embodiments, the transdermalformulation is administered by topical application to the region of skinon the subject without microneedle delivery. In some embodiments, thetransdermal formulation is administered once every hour for an initialperiod of three hours for a total of four applications and thensubsequently administered 3-4 times per day.

In some embodiments, the formulation exhibits a lag effect wherein,following four consecutive hourly applications of the formulation toskin, the amount of cannabidiol delivered through the skin after 21hours is greater than the amount delivered through the skin after 5hours, as assessed in an in vitro permeation study using human cadaverskin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts permeation results of an exemplary formulation of thepresent technology through human cadaver skin using Franz diffusioncells after repeat applications. Results are shown for measurements at2, 4, 6, and 8 hour time-points.

FIG. 2 depicts permeation results of the same exemplary formulation ofthe present technology of FIG. 1 through human cadaver skin using Franzdiffusion cells after repeat applications. Results are shown formeasurements at 2, 4, 6, 8 and 24 hour time-points.

FIG. 3 depicts cannabidiol (CBD) retention results after the 24-hourtime-point shown in FIG. 2.

FIG. 4 depicts permeation results of the same exemplary formulation ofthe present technology of FIG. 1 compared to a marketed formulation(denoted as marketed competitor) through human cadaver skin using Franzdiffusion cells. Results are shown for measurements at 4, 6, 8, and22-hour time-points.

FIG. 5 depicts CBD retention results after the 22-hour time-point shownin FIG. 4.

FIG. 6 depicts self-reported pain scores in an open label study fortreatment of joint and/or muscle pain.

DETAILED DESCRIPTION

Various embodiments are described hereinafter. It should be noted thatthe specific embodiments are not intended as an exhaustive descriptionor as a limitation to the broader aspects discussed herein. One aspectdescribed in conjunction with a particular embodiment is not necessarilylimited to that embodiment and can be practiced with any otherembodiment(s).

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the elements (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the embodiments and does not pose alimitation on the scope of the claims unless otherwise stated. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential.

As used herein, “subject” refers to an animal, such as a mammal(including a human), that has been or will be the object of treatment,observation or experiment. “Subject” and “patient” may be usedinterchangeably, unless otherwise indicated. Mammals include, but arenot limited to, mice, rodents, rats, simians, humans, farm animals,dogs, cats, sport animals, and pets. The methods described herein may beuseful in human therapy and/or veterinary applications. In someembodiments, the subject is a mammal. In some embodiments, the subjectis a human.

The terms “therapeutically effective amount” and “effective amount” areused interchangeably and refer to an amount of a compound that issufficient to effect treatment as defined below, when administered to apatient (e.g., a human) in need of such treatment in one or more doses.The therapeutically effective amount will vary depending upon thepatient, the disease being treated, the weight and/or age of thepatient, the severity of the disease or disorder, or the manner ofadministration as determined by a qualified prescriber or caregiver.

The term “treatment” or “treating” means administering a formulationdisclosed herein for the purpose of: (i) delaying the onset of adisease/disorder, that is, causing the clinical symptoms of thedisease/disorder not to develop or delaying the development thereof (ii)inhibiting the disease/disorder, that is, arresting the development ofclinical symptoms; and/or (iii) relieving the disease/disorder, that is,causing the regression of clinical symptoms or the severity thereof.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, e.g., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration. A pharmaceutically acceptable salt of an active agentcan be used instead of the free base form of the active agent in anyformulation disclosed herein.

As used herein, the term “musculoskeletal” refers to joints, tendons,ligaments, skeletal muscles (e.g., muscles that contract to pull ontendons and move the bones of the skeleton, maintain posture and bodyposition, support soft tissues, guard entrances and exits to thedigestive and urinary tracts; and maintain body temperature), nerves,and cartilage. Accordingly, in some embodiments, musculoskeletalpain/inflammation is located at one or more joints, tendons, ligaments,skeletal muscles, nerves, and cartilage.

As used herein, the term “transdermal” refers to topical application toa skin surface for local and/or systemic effect(s) depending on theactive agent in the formulation.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this present invention belongs. Although any methodsand materials similar or equivalent to those described herein can alsobe used in the practice or testing of the present invention,representative illustrative methods and materials are described herein.

Transdermal Formulations

In one aspect, provided herein are transdermal formulations comprising,consisting essentially of, or consisting of about 0.05% w/w to about 50%w/w synthetic or natural phytocannabinoid and pharmaceuticallyacceptable excipients.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w synthetic or natural phytocannabinoid dispersed in apharmaceutically acceptable carrier comprising, consisting essentiallyof, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w synthetic phytocannabinoid dispersed in apharmaceutically acceptable carrier comprising, consisting essentiallyof, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w natural phytocannabinoid dispersed in apharmaceutically acceptable carrier comprising, consisting essentiallyof, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w hemp-derived phytocannabinoid dispersed in apharmaceutically acceptable carrier comprising, consisting essentiallyof, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 50% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 30% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 10% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 5% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting of about 0.05% w/wto about 1% w/w cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting of:

about 3% w/w to about 30% w/w penetration enhancer,

about 0.8% w/w to about 1.3% w/w thickening agent,

about 0.25% w/w to about 6% w/w buffering agent,

about 0.05% w/w to about 0.08% w/w sequestering agent,

about 0.4% w/w to about 0.8% w/w of preservative, and

up to about 95.45% w/w of deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In another aspect, provided herein are transdermal formulationscomprising, consisting essentially of, or consisting ofmicroencapsulated cannabidiol dispersed in a pharmaceutically acceptablecarrier comprising, consisting essentially of, or consisting ofdeionized water, a penetration enhancer, a thickening agent, a bufferingagent, a sequestering agent, and a preservative.

In another aspect, provided herein are transdermal formulationsconsisting of

about 0.2% w/w cannabidiol,

about 18% w/w diethylene glycol monoethyl ether,

about 1% w/w cross-linked polyacrylic acid polymer,

about 0.3% w/w triethanolamine,

about 0.5% w/w phenoxyethanol,

about 0.05% w/w disodium EDTA dihydrate, and

q.s. deionized water;

wherein the cannabidiol is microencapsulated cannabidiol.

In any embodiments, the formulation disclosed herein may be in the formof a topical formulation. Topical formulations include, but are notlimited to, gels, lotions, creams, ointments, pastes, serums, foams,sprays, powders, or liquids (e.g., suspension or solution). In anyembodiments, the topical formulation may be a semi-solid formulation. Asemi-solid formulation includes, but is not limited to, a gel, a lotion,a cream, an ointment, a suspension, a paste, a serum, and a foam.

In any embodiments, the formulation disclosed herein may be in the formof a lotion, cream, gel, paste, serum, or ointment. In some embodiments,the formulation disclosed herein is a gel.

Phytocannabinoid

The phytocannabinoid may be selected from one or more of cannabidiol(CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN),cannabitriol (CBT), cannabidiolic acid (CBDA), cannabigerolic acid(CBGA), cannabidivarin (CBDV), beta caryophyllene, andtetrahydrocannabinol. In some embodiments, the phytocannabinoid iscannabidiol (CBD). In some embodiments, the phytocannabinoid iscannabigerol (CBG). In some embodiments, the phytocannabinoid iscannabichromene (CBC). In some embodiments, the phytocannabinoid iscannabinol (CBN). In some embodiments, the phytocannabinoid iscannabitriol (CBT). In some embodiments, phytocannabinoid iscannabidiolic acid (CBDA). In some embodiments, the phytocannabinoid iscannabigerolic acid (CBGA). In some embodiments, the phytocannabinoid iscannabidivarin (CBDV). In some embodiments, the phytocannabinoid is betacaryophyllene. In some embodiments, the phytocannabinoid istetrahydrocannabinol. In some embodiments, the phytocannabinoid excludestetrahydrocannabinol.

In any of these embodiments, the phytocannabinoid may be synthetic ornatural. As used herein, a “natural phytocannabinoid” refers to aphytocannabinoid isolated from a natural source, such as a plant. Asused herein, a “synthetic phytocannabinoid” refers to a phytocannabinoidprepared synthetically. In some embodiments, the naturalphytocannibinoid is a hemp-derived phytocannabinoid.

In any of these embodiments, the phytocannabinoid may bemicroencapsulated. In some embodiments, the microencapsulatedphytocannabinoid comprises, consists essentially of, or consists ofphytocannabinoid encapsulated within liposomes. In some embodiments, thephytocannabinoid is not microencapsulated.

In any embodiments, the phytocannabinoid may be present in theformulation disclosed herein in an amount of about 0.05% w/w to about50% w/w. This includes about 0.05% w/w to about 45% w/w, about 0.05% w/wto about 40% w/w, about 0.05% w/w to about 35% w/w, about 0.05% w/w toabout 30% w/w, about 0.05% w/w to about 25% w/w, about 0.05% w/w toabout 20% w/w, about 0.05% w/w to about 15% w/w, about 0.05% w/w toabout 10% w/w, about 0.05% w/w to about 5% w/w, about 0.05% w/w to about4% w/w, about 0.05% w/w to about 3% w/w, about 0.05% w/w to about 2%w/w, about 0.05% w/w to about 1% w/w, about 0.05% w/w to about 0.5% w/w,about 0.1% w/w to about 45% w/w, about 0.1% w/w to about 40% w/w, about0.1% w/w to about 35% w/w, about 0.1% w/w to about 30% w/w, about 0.1%w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w toabout 15% w/w, about 0.1% w/w to about 10% w/w, about 0.1% w/w to about5% w/w, about 0.1% w/w to about 4% w/w, about 0.1% w/w to about 3% w/w,about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w, about0.1% w/w to about 0.5% w/w, about 1% w/w to about 45% w/w, about 1% w/wto about 40% w/w, about 1% w/w to about 35% w/w, about 1% w/w to about30% w/w, about 1% w/w to about 25% w/w, about 1% w/w to about 20% w/w,about 1% w/w to about 15% w/w, about 1% w/w to about 10% w/w, about 1%w/w to about 5% w/w, about 5% w/w to about 45% w/w, about 5% w/w toabout 40% w/w, about 5% w/w to about 35% w/w, about 5% w/w to about 30%w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, 10% w/w to about50% w/w, 10% w/w to about 45% w/w, about 10% w/w to about 40% w/w, about10% w/w to about 35% w/w, about 10% w/w to about 30% w/w, about 10% w/wto about 25% w/w, about 10% w/w to about 20% w/w, and about 10% w/w toabout 15% w/w. Thus, the phytocannabinoid may be present in theformulation disclosed herein in an amount of about 0.05, 0.06, 0.07,0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% w/w, including incrementstherein.

In any embodiments, the phytocannabinoid may be present in theformulation disclosed herein in an amount of about 50 mg to about 500mg. This includes about 50 mg to about 100 mg, 50 mg to about 125 mg, 50mg to about 150 mg, 50 mg to about 175 mg, 50 mg to about 200 mg, 50 mgto about 225 mg, 50 mg to about 250 mg, 50 mg to about 275 mg, 50 mg toabout 300 mg, 50 mg to about 325 mg, 50 mg to about 350 mg, 50 mg toabout 375 mg, 50 mg to about 400 mg, 50 mg to about 425 mg, 50 mg toabout 450 mg, 50 mg to about 475 mg; 100 mg to about 125 mg, 100 mg toabout 150 mg, 100 mg to about 175 mg, 100 mg to about 200 mg, 100 mg toabout 225 mg, 100 mg to about 250 mg, 100 mg to about 275 mg, 100 mg toabout 300 mg, 100 mg to about 325 mg, 100 mg to about 350 mg, 100 mg toabout 375 mg, 100 mg to about 400 mg, 100 mg to about 425 mg, 100 mg toabout 450 mg, 100 mg to about 475 mg, and 100 mg to about 500 mg. Thus,the phytocannabinoid may be present in the formulation disclosed hereinin an amount of about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 130,135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340,350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480,490, or 500 mg, including increments therein.

In any embodiments, the phytocannabinoid may be present in theformulation disclosed herein in an amount of about 1 mg/mL to about 500mg/mL. This includes about 1 mg/mL to about 25 mg/mL; about 1 mg/mL toabout 50 mg/mL; about 1 mg/mL to about 75 mg/mL; about 1 mg/mL to about100 mg/mL, 1 mg/mL to about 125 mg/mL, 1 mg/mL to about 150 mg/mL, 1mg/mL to about 175 mg/mL, 1 mg/mL to about 200 mg/mL, 1 mg/mL to about225 mg/mL, 1 mg/mL to about 250 mg/mL, 1 mg/mL to about 275 mg/mL, 1mg/mL to about 300 mg/mL, 1 mg/mL to about 325 mg/mL, 1 mg/mL to about350 mg/mL, 1 mg/mL to about 375 mg/mL, 1 mg/mL to about 400 mg/mL, 1mg/mL to about 425 mg/mL, 1 mg/mL to about 450 mg/mL, 1 mg/mL to about475 mg/mL; about 25 mg/mL to about 50 mg/mL, about 25 mg/mL to about 75mg/mL, about 25 mg/mL to about 100 mg/mL, 25 mg/mL to about 125 mg/mL,25 mg/mL to about 150 mg/mL, 25 mg/mL to about 175 mg/mL, 25 mg/mL toabout 200 mg/mL, 25 mg/mL to about 225 mg/mL, 25 mg/mL to about 250mg/mL, 25 mg/mL to about 275 mg/mL, 25 mg/mL to about 300 mg/mL, 25mg/mL to about 325 mg/mL, 25 mg/mL to about 350 mg/mL, 25 mg/mL to about375 mg/mL, 25 mg/mL to about 400 mg/mL, 25 mg/mL to about 425 mg/mL, 25mg/mL to about 450 mg/mL, 25 mg/mL to about 475 mg/mL; about 50 mg/mL toabout 100 mg/mL, 50 mg/mL to about 125 mg/mL, 50 mg/mL to about 150mg/mL, 50 mg/mL to about 175 mg/mL, 50 mg/mL to about 200 mg/mL, 50mg/mL to about 225 mg/mL, 50 mg/mL to about 250 mg/mL, 50 mg/mL to about275 mg/mL, 50 mg/mL to about 300 mg/mL, 50 mg/mL to about 325 mg/mL, 50mg/mL to about 350 mg/mL, 50 mg/mL to about 375 mg/mL, 50 mg/mL to about400 mg/mL, 50 mg/mL to about 425 mg/mL, 50 mg/mL to about 450 mg/mL, 50mg/mL to about 475 mg/mL; 100 mg/mL to about 125 mg/mL, 100 mg/mL toabout 150 mg/mL, 100 mg/mL to about 175 mg/mL, 100 mg/mL to about 200mg/mL, 100 mg/mL to about 225 mg/mL, 100 mg/mL to about 250 mg/mL, 100mg/mL to about 275 mg/mL, 100 mg/mL to about 300 mg/mL, 100 mg/mL toabout 325 mg/mL, 100 mg/mL to about 350 mg/mL, 100 mg/mL to about 375mg/mL, 100 mg/mL to about 400 mg/mL, 100 mg/mL to about 425 mg/mL, 100mg/mL to about 450 mg/mL, 100 mg/mL to about 475 mg/mL, and 100 mg/mL toabout 500 mg/mL. Thus, the active agent may be present in theformulation disclosed herein in an amount of about 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120,121, 122, 123, 124, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170,175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280,290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420,430, 440, 450, 460, 470, 480, 490, or 500 mg/mL, including incrementstherein.

In some embodiments, the phytocannabinoid is or comprises cannabidiol,which may be present in the formulation disclosed herein in an amount ofabout 0.5% w/w to about 50% w/w. This includes about 0.05% w/w to about45% w/w, about 0.05% w/w to about 40% w/w, about 0.05% w/w to about 35%w/w, about 0.05% w/w to about 30% w/w, about 0.05% w/w to about 25% w/w,about 0.05% w/w to about 20% w/w, about 0.05% w/w to about 15% w/w,about 0.05% w/w to about 10% w/w, about 0.05% w/w to about 5% w/w, about0.05% w/w to about 4% w/w, about 0.05% w/w to about 3% w/w, about 0.05%w/w to about 2% w/w, about 0.05% w/w to about 1% w/w, about 0.05% w/w toabout 0.5% w/w, about 0.1% w/w to about 45% w/w, about 0.1% w/w to about40% w/w, about 0.1% w/w to about 35% w/w, about 0.1% w/w to about 30%w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w,about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about0.1% w/w to about 5% w/w, about 0.1% w/w to about 4% w/w, about 0.1% w/wto about 3% w/w, about 0.1% w/w to about 2% w/w, about 0.1% w/w to about1% w/w, about 0.1% w/w to about 0.5% w/w, about 1% w/w to about 45% w/w,about 1% w/w to about 40% w/w, about 1% w/w to about 35% w/w, about 1%w/w to about 30% w/w, about 1% w/w to about 25% w/w, about 1% w/w toabout 20% w/w, about 1% w/w to about 15% w/w, about 1% w/w to about 10%w/w, about 1% w/w to about 5% w/w, about 5% w/w to about 45% w/w, about5% w/w to about 40% w/w, about 5% w/w to about 35% w/w, about 5% w/w toabout 30% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 20%w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, 10%w/w to about 45% w/w, about 10% w/w to about 40% w/w, about 10% w/w toabout 35% w/w, about 10% w/w to about 30% w/w, about 10% w/w to about25% w/w, about 10% w/w to about 20% w/w, and about 10% w/w to about 15%w/w. In some embodiments, cannabidiol is present in the formulationdisclosed herein in an amount of about 0.05, 0.06, 0.07, 0.08, 0.09,0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, or 50% w/w, including increments therein.

In some embodiments, the phytocannabinoid is or comprises cannabidiol,which may be present in the formulation disclosed herein in an amount ofabout 50 mg to about 500 mg. This includes about 50 mg to about 100 mg,50 mg to about 125 mg, 50 mg to about 150 mg, 50 mg to about 175 mg, 50mg to about 200 mg, 50 mg to about 225 mg, 50 mg to about 250 mg, 50 mgto about 275 mg, 50 mg to about 300 mg, 50 mg to about 325 mg, 50 mg toabout 350 mg, 50 mg to about 375 mg, 50 mg to about 400 mg, 50 mg toabout 425 mg, 50 mg to about 450 mg, 50 mg to about 475 mg; 100 mg toabout 125 mg, 100 mg to about 150 mg, 100 mg to about 175 mg, 100 mg toabout 200 mg, 100 mg to about 225 mg, 100 mg to about 250 mg, 100 mg toabout 275 mg, 100 mg to about 300 mg, 100 mg to about 325 mg, 100 mg toabout 350 mg, 100 mg to about 375 mg, 100 mg to about 400 mg, 100 mg toabout 425 mg, 100 mg to about 450 mg, 100 mg to about 475 mg, and 100 mgto about 500 mg. In some embodiments, cannabidiol is present in theformulation disclosed herein in an amount of about 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120,121, 122, 123, 124, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170,175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280,290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420,430, 440, 450, 460, 470, 480, 490, or 500 mg, including incrementstherein.

In any embodiments, the phytocannabinoid is or comprises cannabidiol,which may be present in the formulation disclosed herein in an amount ofabout 1 mg/mL to about 500 mg/mL. This includes about 1 mg/mL to about25 mg/mL; about 1 mg/mL to about 50 mg/mL; about 1 mg/mL to about 75mg/mL; about 1 mg/mL to about 100 mg/mL, 1 mg/mL to about 125 mg/mL, 1mg/mL to about 150 mg/mL, 1 mg/mL to about 175 mg/mL, 1 mg/mL to about200 mg/mL, 1 mg/mL to about 225 mg/mL, 1 mg/mL to about 250 mg/mL, 1mg/mL to about 275 mg/mL, 1 mg/mL to about 300 mg/mL, 1 mg/mL to about325 mg/mL, 1 mg/mL to about 350 mg/mL, 1 mg/mL to about 375 mg/mL, 1mg/mL to about 400 mg/mL, 1 mg/mL to about 425 mg/mL, 1 mg/mL to about450 mg/mL, 1 mg/mL to about 475 mg/mL; about 25 mg/mL to about 50 mg/mL,about 25 mg/mL to about 75 mg/mL, about 25 mg/mL to about 100 mg/mL, 25mg/mL to about 125 mg/mL, 25 mg/mL to about 150 mg/mL, 25 mg/mL to about175 mg/mL, 25 mg/mL to about 200 mg/mL, 25 mg/mL to about 225 mg/mL, 25mg/mL to about 250 mg/mL, 25 mg/mL to about 275 mg/mL, 25 mg/mL to about300 mg/mL, 25 mg/mL to about 325 mg/mL, 25 mg/mL to about 350 mg/mL, 25mg/mL to about 375 mg/mL, 25 mg/mL to about 400 mg/mL, 25 mg/mL to about425 mg/mL, 25 mg/mL to about 450 mg/mL, 25 mg/mL to about 475 mg/mL;about 50 mg/mL to about 100 mg/mL, 50 mg/mL to about 125 mg/mL, 50 mg/mLto about 150 mg/mL, 50 mg/mL to about 175 mg/mL, 50 mg/mL to about 200mg/mL, 50 mg/mL to about 225 mg/mL, 50 mg/mL to about 250 mg/mL, 50mg/mL to about 275 mg/mL, 50 mg/mL to about 300 mg/mL, 50 mg/mL to about325 mg/mL, 50 mg/mL to about 350 mg/mL, 50 mg/mL to about 375 mg/mL, 50mg/mL to about 400 mg/mL, 50 mg/mL to about 425 mg/mL, 50 mg/mL to about450 mg/mL, 50 mg/mL to about 475 mg/mL; 100 mg/mL to about 125 mg/mL,100 mg/mL to about 150 mg/mL, 100 mg/mL to about 175 mg/mL, 100 mg/mL toabout 200 mg/mL, 100 mg/mL to about 225 mg/mL, 100 mg/mL to about 250mg/mL, 100 mg/mL to about 275 mg/mL, 100 mg/mL to about 300 mg/mL, 100mg/mL to about 325 mg/mL, 100 mg/mL to about 350 mg/mL, 100 mg/mL toabout 375 mg/mL, 100 mg/mL to about 400 mg/mL, 100 mg/mL to about 425mg/mL, 100 mg/mL to about 450 mg/mL, 100 mg/mL to about 475 mg/mL, and100 mg/mL to about 500 mg/mL. Thus, the active agent may be present inthe formulation disclosed herein in an amount of about 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,120, 121, 122, 123, 124, 125, 130, 135, 140, 145, 150, 155, 160, 165,170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270,280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410,420, 430, 440, 450, 460, 470, 480, 490, or 500 mg/mL, includingincrements therein.

In some embodiments, the cannabidiol is microencapsulated cannabidiol.In some embodiments, the microencapsulated cannabidiol comprises,consists essentially of, or consists of cannabidiol encapsulated withinliposomes. Microencapsulated cannabidiol can be obtained through methodsknown in the art or from commercially available sources. Onenon-limiting example of a commercially available microencapsulatedcannabidiol is CEBIDIOL™ (Isodiol International Inc.).

Penetration Enhancer

As noted above, the formulations described herein include a penetrationenhancer. In some embodiments, the penetration enhancer is selected fromdiethylene glycol monoethyl ether, lauryl alcohol, dimethyl sulfoxide(DMSO), dimethyl acetamide, N-methyl pyrrolidone, oleic acid, azone,oxazolidinone derivatives, urea, terpenes (including, but not limitedto, menthol, linalyl alcohol, eugenol, limonene, pinene, and squalene),or any combination thereof.

In some embodiments, the penetration enhancer comprises, consistsessentially of, or consists of diethylene glycol monoethyl ether.

In some embodiments, the penetration enhancer is present in theformulation disclosed herein in an amount of about 3% w/w to about 30%w/w. This includes about 3% w/w to about 25% w/w, about 3% w/w to about20% w/w, about 5% w/w to about 30% w/w, about 5% w/w to about 25% w/w,about 5% w/w to about 20% w/w, about 8% w/w to about 30% w/w, about 8%w/w to about 25% w/w, about 8% w/w to about 20% w/w, about 10% w/w toabout 30% w/w, about 10% w/w to about 25% w/w, about 10% w/w to about20% w/w, about 15% w/w to about 30% w/w, about 15% w/w to about 25% w/w,and about 15% w/w to about 20% w/w. In some embodiments, the penetrationenhancer is present in the formulation disclosed herein in an amount ofabout 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% w/w, including incrementstherein. In some embodiments, the penetration enhancer is present in theformulation disclosed herein in an amount of about 18% w/w.

Thickening Agent

As noted above, the formulations described herein include a thickeningagent. In some embodiments, the thickening agent is selected from across-linked polyacrylic acid polymer (e.g., a carbomer); a cellulosederivative (e.g., hydroxyethylcellulose, ethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose);xanthan gum, locust beam gum, guar gum or derivative thereof alginicacid; inorganic polymer (such as Weegum, a silicate of aluminum andmagnesium); PEMULEN™ (a copolymer of acrylic acid and C10-C30 alkylacrylate cross-linked with allyl pentaerythritol); or any combinationthereof.

In some embodiments, the thickening agent comprises, consistsessentially of, or consists of a cross-linked polyacrylic acid polymer.In some embodiments, the cross-linked polyacrylic acid polymer is acarbomer. Commercial carbomers include, but are not limited to,CARBOPOL® polymers such as CARBOPOL® Ultrez 10 NF, CARBOPOL® Ultrez 20,CARBOPOL® ETD 2020 NF, CARBOPOL® 71G NF, CARBOPOL® 971P NF, CARBOPOL®974P NF, CARBOPOL® 980 NF, CARBOPOL® 981 NF, and CARBOPOL® 5984 EP.CARBOPOL® Ultrez 10 NF and CARBOPOL® ETD 2020 NF are carbomerhomopolymers or copolymers that contain a block copolymer ofpolyethylene glycol and a long chain alkyl acid ester.

In some embodiments, the thickening agent is present in the formulationdisclosed herein in an amount of about 0.8% w/w to about 1.3% w/w. Thisincludes about 0.8% w/w to about 1.2% w/w, about 0.8% w/w to about 1.1%w/w, about 0.8% w/w to about 1.0% w/w, about 0.9% w/w to about 1.3% w/w,about 0.9% w/w to about 1.2% w/w, about 0.9% w/w to about 1.1% w/w,about 1.0% w/w to about 1.3% w/w, and about 1.0% w/w to about 1.2% w/w.In some embodiments, the thickening agent is present in the formulationdisclosed herein in an amount of about 0.8, 0.9, 1.0, 1.1, 1.2, or 1.3%w/w, including increments therein. In some embodiments, the thickeningagent is present in the formulation disclosed herein in an amount ofabout 1% w/w.

Buffering Agent

As noted above, the formulations described herein include a bufferingagent. In some embodiments, the buffering agent is selected fromtriethanolamine, sodium hydroxide, potassium hydroxide,cocoamidodiethylamine, or any combination thereof.

In some embodiments, the buffering agent comprises, consists essentiallyof, or consists of triethanolamine.

In some embodiments, the buffering agent is present in the formulationdisclosed herein in an amount of about 0.25% w/w to about 6% w/w. Thisincludes about 0.25% w/w to about 5% w/w, about 0.25% w/w to about 4%w/w, about 0.25% w/w to about 3% w/w, about 0.25% w/w to about 2% w/w,about 0.25% w/w to about 1% w/w, about 0.5% w/w to about 6% w/w, 0.5%w/w to about 5% w/w, about 0.5% w/w to about 4% w/w, about 0.5% w/w toabout 3% w/w, about 0.5% w/w to about 2% w/w, and about 0.5% w/w toabout 1% w/w. In some embodiments, the buffering agent is present in theformulation disclosed herein in an amount of about 0.25, 0.30, 0.35,0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95,1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75,4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, or 6.00% w/w, includingincrements therein.

Sequestering Agent

As noted above, the formulations described herein include a sequesteringagent. In some embodiments, the sequestering agent is selected fromEDTA, or a salt and/or solvate thereof citric acid; tartaric acid; orany combination thereof.

In some embodiments, the sequestering agent comprises, consistsessentially of, or consists of EDTA, or a salt and/or solvate thereof.

In some embodiments, the sequestering agent is present in theformulation disclosed herein in an amount of about 0.05% w/w to about0.08% w/w. This includes about 0.05% w/w to about 0.07% w/w, about 0.06%w/w to about 0.08% w/w, about 0.06% w/w to about 0.07% w/w, and about0.07% w/w to about 0.08% w/w. In some embodiments, the sequesteringagent is present in the formulation disclosed herein in an amount ofabout 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, or 0.08% w/w, includingincrements therein.

Preservative

As noted above, the formulations described herein include apreservative. In some embodiments, the preservative is selected fromphenoxyethanol, urea derivatives (such as, but not limited to,diazolidinyl urea and imidazolidinyl urea), ethylhexylglycerine,hydantoin, benzoic, sorbic acid, anisic acid, or any combinationthereof.

In some embodiments, the preservative comprises, consists essentiallyof, or consists of phenoxyethanol.

In some embodiments, the preservative is present in the formulationdisclosed herein in an amount of about 0.4% w/w to about 0.8% w/w. Thisincludes about 0.4% w/w to about 0.7% w/w, about 0.4% w/w to about 0.6%w/w, about 0.4% w/w to about 0.5% w/w, about 0.5% w/w to about 0.8% w/w,about 0.5% w/w to about 0.7% w/w, about 0.5% w/w to about 0.6% w/w,about 0.6% w/w to about 0.8% w/w, about 0.6% w/w to about 0.7% w/w, andabout 0.7% w/w to about 0.8% w/w. In some embodiments, the preservativeis present in the formulation disclosed herein in an amount of about0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8% w/w, includingincrements therein.

Other Components

The formulations described herein may include one or more othercomponents suitable for use in a transdermal composition. Deionizedwater is added to the formulation as needed (q.s.). The formulationsdescribed herein comprise, consist essentially of, or consist of up toabout 95.45% w/w deionized water. This includes about 11.82% w/w toabout 95.45% w/w and ranges in between. In some embodiments, theformulation comprises, consists essentially of, or consists of 79.5% w/wdeionized water.

The formulations described herein are alcohol-free. The term“alcohol-free” as it pertains to a formulation described herein meansthat the formulation is formulated without methanol, ethanol,iso-propanol, n-propanol, tert-butanol, n-butanol, and other alcohols ofsimilarly low boiling point.

Delivery Profile

In some embodiments, the formulation disclosed herein exhibits adelivery profile that includes a lag effect wherein, following fourconsecutive hourly applications of the formulation to skin, the amountof phytocannabinoid delivered through the skin after 21 hours is greaterthan the amount delivered through the skin after 5 hours, as assessed inan in vitro permeation study using human cadaver skin. In someembodiments, the formulation disclosed herein exhibits a deliveryprofile that includes a lag effect wherein, following four consecutivehourly applications of the formulation to skin, the amount ofcannabidiol delivered through the skin after 21 hours is greater thanthe amount delivered through the skin after 5 hours, as assessed in anin vitro permeation study using human cadaver skin.

In some embodiments, the formulation disclosed herein exhibits a lageffect wherein, following three consecutive hourly applications of theformulation to skin, the amount of phytocannabinoid delivered throughthe skin after 22 hours is greater than the amount delivered through theskin after 5 hours, as assessed in an in vitro permeation study usinghuman cadaver skin. In some embodiments, the formulation disclosedherein exhibits a lag effect wherein, following three consecutive hourlyapplications of the formulation to skin, the amount of cannabidioldelivered through the skin after 22 hours is greater than the amountdelivered through the skin after 5 hours, as assessed in an in vitropermeation study using human cadaver skin.

In some embodiments, the formulation transdermally deliversphytocannabinoid to skin in an amount of at least 15, 16, 17, 18, 19,20, 21, 22, or 23 μg/cm² of skin, as assessed in an in vitro retentionstudy using human cadaver skin after 24 hours following an initialapplication of the formulation to the skin. In some embodiments, theformulation transdermally delivers cannabidiol to skin in an amount ofat least 15, 16, 17, 18, 19, 20, 21, 22, or 23 μg/cm² of skin, asassessed in an in vitro retention study using human cadaver skin after24 hours following an initial application of the formulation to theskin.

Without being bound to any one particular theory, it is believed thatlipophilicity of the formulation of the present technology is modulatedsuch that phytocannabinoid in the formulation can permeate into theskin, accumulate within the skin, and then be delivered through theskin, thereby exhibiting a lag effect as described herein.

Methods of Treatment

In another aspect, provided herein are methods of treating pain and/orinflammation in a subject in need thereof, the methods comprising,consisting essentially of, or consisting of topically administering toone or more regions of skin on the subject a therapeutically effectiveamount of a transdermal formulation disclosed herein.

In another aspect, provided herein are methods of treating pain in asubject in need thereof, the methods comprising, consisting essentiallyof, or consisting of topically administering to one or more regions ofskin on the subject a therapeutically effective amount of a transdermalformulation disclosed herein.

In another aspect, provided herein are methods of treating inflammationin a subject in need thereof, the methods comprising, consistingessentially of, or consisting of topically administering to one or moreregions of skin on the subject a therapeutically effective amount of atransdermal formulation disclosed herein.

In another aspect, provided herein are methods of treatingmusculoskeletal pain and/or inflammation in a subject in need thereof,the methods comprising, consisting essentially of, or consisting oftopically administering to one or more regions of skin on the subject atherapeutically effective amount of a transdermal formulation disclosedherein.

In some embodiments, the musculoskeletal pain and/or inflammation islocated at one or more of the foot, ankle, knee, hip, hand, wrist,elbow, neck, scalp, back, chest, abdomen, shoulder, arm, or leg, of thesubject.

In another aspect, provided herein are methods for relieving painassociated with osteoarthritis of one or more joints in a subject inneed thereof, the methods comprising, consisting essentially of, orconsisting of topically administering a therapeutically effective amountof a transdermal formulation disclosed herein to one or more regions ofskin covering the one or more joints on the subject.

In some embodiments, the one or more joints are located at one or moreof the foot, ankle, knee, hip, hand, wrist, elbow, neck, back, orshoulder of the subject.

In some embodiments, the transdermal formulation disclosed herein isadministered by topical application to the region of skin on the subjectwithout microneedle delivery.

In some embodiments, the transdermal formulation disclosed herein isadministered once every hour for an initial period of two hours for atotal of three applications and then subsequently administered 3-4 timesper day. In some embodiments, the transdermal formulation disclosedherein is administered once every hour for an initial period of threehours for a total of four applications and then subsequentlyadministered 3-4 times per day. In some embodiments, the transdermalformulation disclosed herein is administered once every hour for aninitial period of four hours for a total of five applications and thensubsequently administered 3-4 times per day.

Packaging

The formulations disclosed herein may be provided in any suitablecontainer, such as a jar, a tube, or a container with a pump dispenser,optionally, a unit dose pump dispenser. In some embodiments, theformulation disclosed herein is provided in a container with a medicalgrade pump dispenser, optionally, a unit dose pump dispenser. In someembodiments, the formulation disclosed herein is provided in a containerwith a medical grade pump dispenser with a cooling tip, optionally, aunit dose pump dispenser.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES Example 1

Formulation of Cannabidiol (Formulation A100)

Concentration Constituents (% w/w) cannabidiol* 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s. *microencapsulated (CEBIDIOL ™),100 mg CBD/50 mL composition

Example 2

Repeat Application Study—Permeation Assessment

General Protocol

Skin samples from suitable human donors shipped and stored frozen at−20° C. were used. The skins were removed from the freezer and allowedto equilibrate to room temperature. They were then punched with a steelpunch to fit the top of the receptor cell. They were visually examinedunder stereoptic magnifier to confirm the absence of any skin defects.Receptor compartments were filled with the receptor fluid. Skin pieceswere mounted on the receptor cells, the donor compartments were placedon top, and both compartments were clamped together. The skins were thenallowed to hydrate in contact with the receptor fluid for ˜1 hour. Anycells showing leakage were replaced.

Five replicates of each formulation were tested versus controls (e.g.,composition of the present invention versus marketed formulation). Eachtest formulation was applied at a dose of 10 mg and spread uniformlyover a skin sample of 0.55 cm². The Franz cells were maintained at 35°C. and the receptor compartment was continuously stirred with a magneticstir bar. A sample was taken from each receptor compartment atpredetermined time intervals (e.g., 2, 4, 6/8 and 22/24 hour). Thesamples were assayed by HPLC.

In this particular study, the set of cells was divided into 4 groups of5 Franz cells. Approximately 10 mg of Formulation A100 was applied tothe skin of each donor compartment of the cells. The skin was obtainedfrom a human male (63 years old, 158 lbs, back skin, 500 thickness).

Formulation A100 application: The first group of (5) cells was treatedas in Example 2 with no further formulation application.

Formulation A100 application+1 repeat application: In the second groupof (5) cells, after 1 hour, the remaining formulation at the surface ofthe skin samples was first removed and the samples were further wipedand cleaned quickly with a cotton swab. Then, another application ofapproximately 10 mg of formulation was applied.

Formulation A100 application+2 repeat applications: In the third groupof (5) cells, after each of 1 hour and 2 hours, the remainingformulation at the surface of the skin samples was first removed and thesamples were further wiped and cleaned quickly with a cotton swab, andthen further applications of approximately 10 mg of formulation werere-applied.

Formulation A100 application+3 repeat applications: In the fourth groupof (5) cells, after each of 1 hour, 2 hours, and 3 hours, the remainingformulation at the surface of the skin samples was first removed and thesamples were further wiped and cleaned quickly with a cotton swab, andthen further applications of approximately 10 mg of formulation werere-applied.

A sample was taken from each receptor compartment at predetermined times(2, 4, 6, 8, and 24 hours) in all study groups. All samples wereanalyzed by HPLC.

Results are shown in FIG. 1 and FIG. 2. Although administration of 3repeat applications demonstrates the highest permeated amount after 8hours, the permeated amount remains low (approximately 0.3 μg/cm² orless), as are the permeation amounts for the single application, 1repeat-application and 2-repeat application (FIG. 1). Unexpectedly, thepermeation values display a 16-fold to 30-fold increase after 24 hours(FIG. 2). Lag time was determined to be 3.3 hours. (Lag time is theintercept of steady-state absorption flux straight line with the timeline axis which takes place after absorption has started. It reflectsthe delayed absorption into viable tissue related to the penetrationinto the stratum corneum. Direct lag time measurement in vivo is notpossible but is estimated by extrapolation of the linear portion of thepermeation plot to the time axis.)

Example 3

Repeat Application Study—Retention Assessment

Skin samples were assayed to determine the amount of active agentretained in the skin as follows. After 24 hours of the permeation studyof Example 2, the skin pieces were first wiped clean with cotton swabsand inspected visually to ensure that no formulation remained. The skinpieces were carefully and quickly wiped twice with Ethanol/water (80:20)impregnated cotton swabs and blotted dry each time with Kimwipes(cellulose cloths). The skins were placed into capped 1.5-dram vials towhich 2 ml of ethanol (100%) were added and then sealed with Parafilm(paraffin wax). The vials were stirred overnight at 35° C. to allow theretained active agent to be extracted into ethanol. After cooling toroom temperature, the samples were centrifuged and the supernatant wasanalyzed by HPLC.

Results are shown in FIG. 3. No significant skin retention differencesacross the different treatment groups were observed after 24 hours.

Example 4

Comparative Permeation Study

For this study, skin pieces from a human female (66 years old, 155 lbs,back skin, 250 μm thickness), shipped and stored frozen at −20° C. wereused, and prepared as described in Example 2.

Five replicates of each formulation were tested versus control(Formulation A100 versus marketed formulation). Each test formulationwas applied at a dose of 10 mg and spread uniformly. The Franz cellswere maintained at 35° C. and the receptor compartment was continuouslystirred with a magnetic stir bar. A sample was taken from each receptorcompartment at predetermined time intervals (preferably, 2, 4, 6/8 and22/24 hour). The samples were assayed by HPLC.

The marketed formulation contained hemp extract (includes cannabidiol),camphor, menthol, beeswax, clove oil, cotton, seed oil, eucalyptus oil,jojoba seed oil, peppermint oil, sorbic acid, and tea tree oil.

Results are shown in FIG. 4. The marketed formulation did not show anypermeation as measured up to 8 hours, and showed a small amount ofpermeation after 22 hours.

Retention was assessed as was described in Example 3. Results are shownin FIG. 5. Formulation A100 demonstrated 6-fold higher retention thanthe marketed formulation after 24 hours.

Example 5

Open Label Experiential Study for Joint and/or Muscle Pain

Female subjects between the age of 40-75 years old administeredFormulation A100 (formulation of Example 1) several times daily to treatjoint and/or muscle pain. Each subject completed a questionnaire(designed to record the efficacy of Formulation A100 and various sensoryexperiences) before and after each use of Formulation A100 for 3consecutive days. Interim results (n=32) regarding efficacy as recordedby the questionnaires are presented in FIG. 6. Overall pain scoresdecreased by 4.6 points, an improvement of 69%. Subjects reported thatFormulation A100 applied smoothly and absorbed quickly into the skinwithout leaving a residue.

Example 6

Formulation of Cannabidiol (Formulation A110)

Concentration Constituents (% w/w) cannabigerol 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 7

Formulation of Cannabidiol (Formulation A120)

Concentration Constituents (% w/w) cannabichromene 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 8

Formulation of Cannabidiol (Formulation A1301

Concentration Constituents (% w/w) cannabinol 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 9

Formulation of Cannabidiol (Formulation A140)

Concentration Constituents (% w/w) cannabitriol 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 10

Formulation of Cannabidiol (Formulation A150)

Concentration Constituents (% w/w) cannabidiolic acid 0.2 diethyleneglycol monoethyl ether 18 cross-linked polyacrylic acid polymer 1(CARBOPOL ® Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 11

Formulation of Cannabidiol (Formulation A160)

Concentration Constituents (% w/w) cannabigerolic acid 0.2 diethyleneglycol monoethyl ether 18 cross-linked polyacrylic acid polymer 1(CARBOPOL ® Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 12

Formulation of Cannabidiol (Formulation A170)

Concentration Constituents (% w/w) cannabidivarin 0.2 diethylene glycolmonoethyl ether 18 cross-linked polyacrylic acid polymer 1 (CARBOPOL ®Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

Example 13

Formulation of Cannabidiol (Formulation A180)

Concentration Constituents (% w/w) beta caryophyllene 0.2 diethyleneglycol monoethyl ether 18 cross-linked polyacrylic acid polymer 1(CARBOPOL ® Ultrez 30) triethanolamine 0.3 disodium EDTA dihydrate 0.05phenoxyethanol 0.5 deionized water q.s.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds, or compositions, which can ofcourse vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

What is claimed is:
 1. A transdermal formulation consisting of fromabout 0.05% w/w to about 50% w/w cannabidiol dispersed in apharmaceutically acceptable carrier consisting of: from about 3% w/w toabout 30% w/w penetration enhancer selected from the group consisting ofdiethylene glycol monoethyl ether, lauryl alcohol, dimethyl sulfoxide(DMSO), dimethyl acetamide, N-methyl pyrrolidone, oleic acid, azone,urea, terpene, and combinations of any two or more thereof, from about0.8% w/w to about 1.3% w/w thickening agent selected from the groupconsisting of cross-linked polyacrylic acid polymers;hydroxyethylcellulose, ethyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose; xanthan gum,locust beam gum, guar gum; alginic acid; PEMULEN™ (a copolymer ofacrylic acid and C₁₀-C₃₀ alkyl acrylate cross-linked with allylpentaerythritol); and combinations of any two or more thereof, fromabout 0.25% w/w to about 6% w/w buffering agent selected from the groupconsisting of triethanolamine, potassium hydroxide,cocoamidodiethylamine, and combinations of any two or more thereof, fromabout 0.05% w/w to about 0.08% w/w sequestering agent selected from thegroup consisting of EDTA and salts and solvates thereof; citric acid;tartaric acid; and combinations of any two or more thereof, from about0.4% w/w to about 0.8% w/w of preservative selected from the groupconsisting of phenoxyethanol, ethylhexylglycerine, hydantoin, sorbicacid, anisic acid, and combinations or any two or more thereof, and upto about 95.45% w/w of deionized water; wherein all percentages arebased on the total weight of the formulation; wherein the transdermalformulation is a semi-solid formulation selected from the groupconsisting of a gel, a lotion, a cream, an ointment, a serum, and afoam.
 2. The formulation of claim 1, wherein the penetration enhancer isdiethylene glycol monoethyl ether.
 3. The formulation of claim 1,wherein the thickening agent is a cross-linked polyacrylic acid polymer.4. The formulation of claim 1, wherein the buffering agent istriethanolamine.
 5. The formulation of claim 1, wherein the sequesteringagent is selected from the group consisting of EDTA and salts andsolvates thereof.
 6. The formulation of claim 1, wherein thepreservative is phenoxyethanol.
 7. The formulation of claim 1,consisting of about 0.20% w/w cannabidiol, about 18% w/w diethyleneglycol monoethyl ether, about 1% w/w cross-linked polyacrylic acidpolymer, about 0.3% w/w triethanolamine, about 0.5% w/w phenoxyethanol,about 0.05% w/w disodium EDTA dihydrate, and q.s. deionized water. 8.The formulation of claim 1, wherein the formulation exhibits a lageffect wherein, following four consecutive hourly applications of theformulation to skin, the amount of cannabidiol delivered through theskin after 21 hours is greater than the amount delivered through theskin after 5 hours, as assessed in an in vitro permeation study usinghuman cadaver skin.
 9. A method of treating musculoskeletal pain and/orinflammation in a subject in need thereof, the method comprisingtopically administering to one or more regions of skin on the subject atherapeutically effective amount of a transdermal formulation of claimclaim
 1. 10. The method of claim 9, wherein the transdermal formulationis administered by topical application to the region of skin on thesubject without microneedle delivery.
 11. The method of claim 9, whereinthe transdermal formulation is administered once every hour for aninitial period of three hours for a total of four applications and thensubsequently administered 3-4 times per day.
 12. The method of claim 9,wherein the musculoskeletal pain and/or inflammation is located at oneor more of the foot, ankle, knee, hip, hand, wrist, elbow, neck, scalp,back, chest, abdomen, shoulder, arm, or leg, of the subject.
 13. Amethod for relieving pain associated with osteoarthritis of one or morejoints in a subject in need thereof, the method comprising topicallyadministering a therapeutically effective amount of a transdermalformulation of claim 1 to one or more regions of skin covering the oneor more joints on the subject.
 14. The method of claim 13, wherein theone or more joints are located at one or more of the foot, ankle, knee,hip, hand, wrist, elbow, neck, back, or shoulder of the subject.
 15. Themethod of claim 13, wherein the transdermal formulation is administeredby topical application to the region of skin on the subject withoutmicroneedle delivery.
 16. The method of claim 13, wherein thetransdermal formulation is administered once every hour for an initialperiod of three hours for a total of four applications and thensubsequently administered 3-4 times per day.
 17. A container,comprising: the transdermal formulation of claim 1, and a medical gradepump dispenser to dispense the transdermal formulation.
 18. Thecontainer of claim 17, wherein the medical grade pump dispensercomprises a cooling tip.
 19. The container of claim 17, wherein theformulation consists of: about 0.20% w/w cannabidiol, about 18% w/wdiethylene glycol monoethyl ether, about 1% w/w cross-linked polyacrylicacid polymer, about 0.3% w/w triethanolamine, about 0.5% w/wphenoxyethanol, about 0.05% w/w disodium EDTA dihydrate, and q.s.deionized water.